Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. Immunotherapy has emerged as a viable alternative to conventional therapies. Immunotherapy tends to boost, direct, or restore the patient's immune system to fight cancer by proper recognition of specific antigens displayed by tumor cells on their surface, leading to an enhanced immune response. A major challenge in cancer immunotherapy is the development of vaccine formulations that can elicit a cell-mediated immune response in the face of immunological tolerance to the tumor antigen. The quest for new targets suitable for immunotherapy is an active area of research.' We have demonstrated that MUC4 mucin is overexpressed in PC. Preliminary studies from our group and others have also demonstrated the presence of circulating anfi-MUC4 antibodies in cancer patients where MUC4 is overexpressed (pancreatic and lung cancer). The presence of humoral immune response against MUC4 is evidence supporting the fact that MUC4 is immunogenic in cancer patients and together with the overexpression of this mucin in PC, supports the case of MUC4 as a promising vaccine candidate. The scientific rationale of this grant proposal is to evaluate the potential of MUC4 mucin for the immunotherapy of pancreatic cancer. The overall hypothesis of the proposal is that the encapsulation of MUC4 into amphiphilic polyanhydride nanospheres will provide superior adjuvanticity against PC. To test the hypothesis three specific aims are proposed. Aim 1: Formulation, optimization and ex vivo characterization of MUC4 nanovaccine. Aim 2: In vivo evaluation of MUC4 nanovaccine in syngeneic murine model of pancreatic cancer. Aim 3: Evaluation of MUC4 vaccine in MUC4 transgenic mouse model. Our proposed preclinical studies will establish whether MUC4 is a viable target to be pursued for vaccine development. Further, MUC4 nanovaccine will be evaluated in MUC4 transgenic mice which closely resemble the human situation i.e MUC4 is recognized as a self-antigen. If the results are encouraging, such formulations should be ready to be tested in human subjects within the next 3-4 years.